1. Field of the Invention
The present invention relates to novel methods of preparing a wide variety of spectinomycin analogs and biologically acceptable salts thereof. Further, the invention relates both to novel intermediates and novel products therein. The novel products are spectinomycin analogs which can be used for the same biological purposes as spectinomycin. The processes of the invention provide for novel intermediates that are versatile and highly reactive exocyclic enones having formula I
wherein
R.sub.1 and R.sub.2 are blocking groups, and PA1 R is selected from the group consisting of hydrogen, alkyl of C.sub.1 to C.sub.20, inclusive, lower alkenyl, lower haloalkyl, lower aminoalkyl, lower alkynyl, and --(CH.sub.2).sub.n --OX PA1 X is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, benzyl, and acyl; PA1 n is an integer of from zero to four with the proviso that when n is zero --OX cannot be hydroxy. PA1 R.sub.3 and R.sub.4 are the same and are hydrogen or blocking groups; PA1 R is defined as above, and PA1 --T is selected from the group consisting of --OY, --CHR.sub.5 C(O)R.sub.6, --NH.sub.2, --NHR.sub.5, --NR.sub.5 R.sub.6, --NO.sub.2, --NHNH.sub.2, --N.sub.3, --NR.sub.5 SO.sub.2 R.sub.6, --SH, --SR.sub.5, --S--S--, --CH[C(O)R.sub.5 ][C(O)R.sub.6 ], --C.tbd.N, --CH(CN)R.sub.5, --CH[C(O)R.sub.5 ][C(O)OR.sub.6 ], --CH[C(O)OR.sub.5 ][C(O)OR.sub.6 ], --CR.sub.5 R.sub.6 NO.sub.2, --CR.sub.5 R.sub.6 SO.sub.2 R.sub.7, --CR.sub.5 C(N)C(N) PA1 Y is aryl, --CR.sub.5 .dbd.CHR.sub.6 or --N.dbd.O, and PA1 R.sub.5, R.sub.6, and R.sub.7 are the same or different and are lower alkyl or aryl and biologically acceptable salts thereof. PA1 R.sub.3 and R.sub.4 are the same and are hydrogen or blocking groups; PA1 R is as defined above, and PA1 Q is a nucleophile which comprises PA1 Z is hydrogen, aryl, --N.dbd.O, lower alkyl, lower alkenyl, benzyl or acyl; PA1 b is an integer of one through eight; PA1 R.sub.1, R.sub.2, R and R.sub.3 through R.sub.7 are all as defined above (see Scheme A). PA1 (1) contacting the compound III' with N,N-dimethylformamide-ditertiary-butyl acetal and trifluoroacetic acid in dimethylformamide (TFA/DMF) to obtain compounds having the formula II; PA1 (2) contacting the product of step 1 with sodium cyanoborohydride (NaCNBH.sub.3) in methanol at about pH 4 to provide compound III"; PA1 (3) enolization of compound III" to obtain compound I; PA1 (4) contacting the product of steps 2 or 3 with a nucleophile in the presence of triethylamine (Et.sub.3 N) to obtain compound IVa (see Scheme B). PA1 (1) contacting the compound III' with N,N-dimethylformamide-ditertiary-butyl acetal and trifluoro acetic acid and dimethylformamide to obtain the compound II; PA1 (2) contacting the product of step 1 with sodium cyanoborohydride in methanol at pH 4 and treating the mixture with the nucleophile and triethylamine to give the compound IVa (see Scheme C). PA1 R.sub.5, R.sub.6, and R.sub.7 are the same or different and are lower alkyl or aryl; R.sub.8 is lower alkyl, lower alkenyl, lower haloalkyl, lower aminoalkyl or lower alkynyl; PA1 M.sub.1 is a monovalent metal or ion, and PA1 M.sub.2 is a divalent metal.
wherein
Two methods are provided for the synthesis of the enones I by functionalization of the starting materials, i.e., protected spectinomycin and protected spectinomycin analogs having formula III'. Such functionalization provides for Mannich bases of formula III" either (1) directly or (2) through novel intermediate enamines having formula II. The Mannich bases give rise to the enones I. Finally, either the enones I or the enamines II are reacted with nucleophiles to obtain the wide variety of spectinomycin analogs including the novel products of the present invention.
R.sub.1, R.sub.2, and R in formulae I, II, III', and III" are as described above.
2. Description of the Art
Spectinomycin is a known antibiotic having the formula III. A microbiological preparation may be found in U.S. Pat. No. 3,234,092. A chemical synthesis including the nitrogen protected form, now among the starting materials of the present invention is disclosed in copending U.S. application Ser. No. 150,530, filed May 16, 1980 (Case No. 3563A). Numerous analogs of spectinomycin, including corresponding protected forms also among the present starting materials, are disclosed therein. Therefore, U.S. application Ser. No. 150,530 (Case No. 3463A) is incorporated herein by reference. Additional spectinomycin analogs are found in copending U.S. application Ser. No. 359,006, filed Mar. 17, 1982, now U.S. Pat. No. 4,420,624 (Case 3563A-1); U.S. application Ser. No. 020,073, filed Mar. 13, 1979, now U.S. Pat. No. 4,361,701 (Case No. 3589); U.S. application Ser. No. 312,035, filed Oct. 16, 1981, now U.S. Pat. No. 4,405,797 (Case No. 3763); U.S. application Ser. No. 068,926, filed Aug. 23, 1979, now U.S. Pat. No. 4,282,152 (Case 3660); U.S. application Ser. No. 212,952, filed Dec. 4, 1980, now U.S. Pat. No. 4,337,347 (Case 3660-A); U.S. application No. Ser. No. 212,950, filed Dec. 4, 1980, now U.S. Pat. No. 4,344,822 (Case 3660-B); U.S. application No. Ser. No. 212,943, filed Dec. 4, 1980, now U.S. Pat. No. 4,345,086 (Case 3660-C); U.S. application Ser. No. 285,164, filed July 20, 1981, now U.S. Pat. No. 4,380,651 (Case 3819A); U.S. application Ser. No. 285,165, filed July 20, 1981, now U.S. Pat. No. 4,380,652 (Case 3819); U.S. application Ser. No. 358,957, filed Mar. 17, 1982, now U.S. Pat. No. 4,420,623 (3819-1); U.S. application Ser. No. 359,723, filed Mar. 19, 1982, now abandoned (Case 4034), and U.S. application Ser. No. 314,261, filed Oct. 23, 1981, now abandoned (Case 3718). However, none of these disclosures appreciate the novel processes, novel intermediates, or novel products of the present invention.
In general, preparation of Mannich bases are well known. Representative references of such preparations are March, "The Mannich Reaction", Advanced Organic Chemistry: Reactions, Mechanisms and Structure, pp. 670-672, McGraw-Hill Book Company (1968); Flick, "The Use of a Mannich Base as a Source of an Unsaturated Ketone for Condensations With an Active Methylene Compound", Organic Reactions, Vol. 1, pp. 320-322, New York: John Wiley and Sons, Inc. (1942); Brewster et al. "Alkylations With Tertiary Amines", Organic Reactions, vol. 7, pp. 126-130, New York: John Wiley and Sons, Inc. (1953); Bergman et al. "Robinson's Modification of the Michael Condensation", Organic Reactions, vol. 10, pp. 222-223: New York, John Wiley and Sons, Inc. (1959). However, none of these references makes obvious the present invention.